Allergic reactions are generally immune reactions that are initiated by IgE-dependent stimulation of tissue mast cells and related effector molecules (e.g., basophils). Binding events between cell surface bound IgE molecules and antigen results in rapid release of biological response modifiers which bring about increased vascular permeability, vasodilation, smooth muscle contraction and local inflammation. This sequence of events is termed immediate hypersensitivity and begins rapidly, usually within minutes of exposure in a sensitised individual. In its most severe systemic form, anaphylaxis, such immediate hypersensitivity can bring about asphyxiation, produce cardiovascular collapse, and even result in death. Individuals that are prone to strong immediate hypersensitivity responses are referred to as “atopic”. Clinical manifestations of allergy or atopy include hay fever (rhinitis), asthma, urticaria (hives), skin irritation (e.g., eczema such as chronic eczema), anaphylaxis, and related conditions.
The prevalence of atopy has increased in the developed world since the beginning of the 20th century when allergy prevalence was estimated to be less than 0.1% in Europe, UK and US (Schadewaldt H, 1980, Geschichte der Allergies in vier Dustri-Verlag; as cited by Matthias Wjst, 2009, Allergy Asthma & Clinical Immunology. 5:8). About 30-40% of the world population is now affected by one or more allergic conditions. Asthma, rhinitis, and eczema are now prevalent in developed countries, with allergic disorders being the most common chronic diseases among children in developed countries. For example, more than 25% of infants in Australia today present with eczema, more than 20% of one-year olds are food-sensitised, more than 25% of children have asthma, and more than 40% of adults have a history of allergic rhinitis (Pawnkar R, Walter Canonica G, Holgate S T, Lockey R F, 2001, World Allergy Organization (WAO) White Book on Allergy). Allergies also affect about 20% of all individuals in the United States. Atopy is predicted to increase to about 26 of the Australian population by 2050.
Although childhood asthma often improves during childhood, asthma and rhinitis persist throughout adulthood, with substantial increase in asthma associated mortality for those aged more than 60 years (Martin P E et al., 2011, J. Allergy, Clin. Immmnol. 127:1473-1479).
There is a significant economic burden associated with allergic conditions. For example, in 2007 the associated economic cost in Australia was estimated to be $9.4 billion with an additional $21.3 billion from lost wellbeing (e.g., disability and premature death). In the UK, the total annual expenditure for atopic eczema has been estimated at £465 million (€521 m). In Germany, the total average costs for an atopic eczema patient have been estimated to be about €4400. In the US, the direct and indirect costs of asthma to the US economy were projected to have reached US$20.7 billion in 2010, and the direct cost of treating childhood asthma alone exceeds US$1,100 per patient per annum. The cost of treating incidence of eczema alone in patients aged 0 to 5 years is approximately US$360 per patient per annum with an annual cost of over $400,000 in Australia, €5 million in Western Europe and US$3 million in the US.
Several studies have documented temporal changes in allergy patterns in developed countries, from a prevalence of allergic asthma and hay fever in children (Mullins R J, 2007, Med J Aust. 186: 618-621) toward increasing eczema and food allergies during the last 10 years. In this second wave of the allergy epidemic, 10% of children have some form of food allergy (Osborne N J et al., 2011, J. Clin. Immunol. 127:668-676; Prescott S and Allen K J, 2011, Pediatr. Allergy Immunol. 22:155-160). This changing epidemiology for allergic disorders remains largely unexplained.
As illustrated in panel (A) of FIG. 1 hereof, infants who have moderate to severe eczema are at higher risk of developing food allergies and/or allergic asthma later in life e.g., during childhood, and a significant proportion of these individuals will have atopic or respiratory allergies as adults. This is the so-called “atopic march” or “allergic march” (Martin P E et al., 2011, J. Allergy Clin. Immunol. 127:1473-1479). The current generation with food allergies appear to present with symptoms earlier in life than previous generations having respiratory allergies, and appear less likely to outgrow their allergy during early adulthood (Prescott S and Allen K J, 2011, Pediatr. Allergy Immnol. 22:155-160).
The so-called “hygiene hypothesis” attributes the increase in atopy in developed countries to an increase in the use of antibiotics to treat microbial infections in infancy and/or childhood (Strachan D P, 1989, BMJ, 299:1259-1260; Strachan D P, Harkins L S, Golding J, 1997, Clin. Exp. Allergy. 27:151-155; Renz H and Herz U, 2002, Eur. Respir. J. 19:158-171). According to the hygiene hypothesis, changes in the biodiversity of the microbial environment, human microbiome, and reduced exposure to microbes that regulate the host immune system cause childhood allergy leading to the atopic march e.g., because antibiotics reduce the incidence of microorganisms that are beneficial for a balanced immune system development in addition to reducing the incidence of pathogens (Guarner F et al., 2006, Nat. clin. Pract. Gartroenterol. Hepatol. 3: 275-284).
Selection of an appropriate T-cell population occurs during the early stages of immune responses in naive unsensitised hosts such as neonates and new borns and infants having an undeveloped immune system. If selection favours priming the host immune system toward the induction of allergen-specific TH1 cells, then IgG and IgA responses may ensue. TH1 cells seem to play a role in defense against various microbial antigens including bacterial, viral and fungal infections, and uncontrolled TH1responses are involved in organ-specific autoimmunity e.g., in rheumatoid arthritis, multiple sclerosis, thyroiditis, Crohn's disease, systemic lupus erythematosus, experimental autoimmune uveoretinitis (Dubey et al., 1991, Eur. Cytokine Network, 2:147-152), experimental autoimmune encephalitis (EAE) (Beraud et al., 1991, Cell Immunol. 133:379-389), insulin-dependent diabetes mellitus (Hahn et al., 1987, Eur. J. Immunol. 18:2037-2042), contact dermatitis (Kapsenberg et al., Immunol Today, 12:392-395), and in some chronic inflammatory disorders. The principal inflammatory cytokine produced by TH1 cells is IFN-γ (See, for example, Romragnani, ed, TH1 and TH2 Cells in Health and Disease. Chem. Immunol., Karger, Basel, 63, pp. 158-170 and 187-203 (1996)).
On the other hand, the emergence of TH2 cells can lead to IgE production and eosinophilia and ultimately atopic disease. See e.g., WO2005/030249. Allergy, asthma, eczema, psoriasis, allergic rhinitis, hay fever and atopic dermatitis are each associated with a profound immunological deregulation characterized by over production of TH2 cells (Romragnani, supra; van der Heijden et al., 1991; J Invest Derm. 97:389-394; Walker et al., 1992, Am. Rev. Resp. Dis. 148:109-115; and Renz H and Herz U, 2002, supra), and uncontrolled TH2 type responses are responsible for triggering allergic disorders against environmental allergens and chemical allergens. TH2 type responses are also preferentially induced in certain primary immune deficiencies such as hyper-IgE syndrome (Del Prete et al., 1989, J. Clin. Invest. 84:1830-1835) and Omenn's syndrome (Schandene et al., 1993, Eur. J. Immunol. 23:56-60).
TH2 effector functions may be negatively regulated by TH1 cells. The hygiene hypothesis suggests that a reduced frequency of microbial infections, less severe infection, and prevention of infection e.g., by frequent use of antibiotics may prevent maturation of TH1 immunity, and give rise to allergen-specific TH-2 immune responses following subsequent exposure to allergens (Renz H and Herz U, 2002, supra).
There is currently no cure, and only limited treatment, for severe atopy. Treatment options are generally restricted to use of steroids, anti-histamines, immune modulation drugs and administration of adrenalin. At best these treatment regimens provide temporary relief and are generally not suitable for sustained use. Accordingly, there remains an unmet need in the art for compositions and methods for prevention of allergic disorders.
H. pylori is a gastric bacterial pathogen that chronically infects more than half of the world's human population. Infection with H. pylori is usually acquired early in childhood and, if left untreated, can last for a life time with the majority of infected individuals remaining asymptomatic. On the other hand, H. pylori infection is the main cause of peptic ulcer disease, which is manifested in more than 10% of infected subjects (Kuipers et al., 1995. Aliment Plarmacol Ther, 9 Suppl 2: 59-69). H. pylori infection is also associated with an increased risk of non-cardiac gastric adenocarcinoma which is one of the most frequently lethal malignancies, and with gastric mucosa-associated lymphoid tissue (MALT) lymphoma (Suerbaum & Michetti, 2002, N Engl J Med, 347: 1175-1186; Atherton (2006), Annu Rev Pathol. 1:63-96), as well as chronic urticaria (hives).
Epidemiological population studies suggest that prevalence of live H. pylori in the gastric mucosa is inversely-proportional to the incidence of allergy in developed countries. See e.g., Zevit et al., (2011), Helicobacter, 17: 30-35; Shiotani et al., (2008). BMJ, 320: 412-7. Chen & Blaser (2007), Arch Intern Med, 167: 281-7; McCune et al., (2003), Eur J Gastroenterol Hepatol, 15: 637-40; Reibman et al., (2008), PLoS ONE, 3: e4060; Konturek et al., (2008), Med Sci Monit, 14:CR453-8. However, a number of other studies have suggested that the correlation between falling H. pylori infection rates and raising allergy rates might not be correct. See, e.g., Zevit et al., (2011) supra; Raj et al. (2009), J Infect Dis, 199:914-5. These conflicting reports suggest uncertainty as to whether or not reduced colonization of the gastric mucosa by H. pylori is directly involved in the atopic march.